PROJECT SUMMARY Gastrointestinal (GI) health is essential for overall body health, yet many gaps exist in our understanding of how GI tract is protected from infection. The GI tract is highly innervated to coordinate complex physiological responses related to food intake, digestion and absorption. Besides food, the GI tract is the entry site for microbes and parasites, but it is well protected by the local immune system. Comparison of the evolutionary and embryonic development of intestinal immune and nervous systems suggests that two systems must be integrated in their common goal to provide the best functional performance and protection of the GI tract. However, not much is known about the anatomical organization, mechanisms and driving force of neuro- immune interactions. The questions that we ask in this proposal are why and how intestinal nervous and immune systems regulate each other?s functions in response to infection. Macrophages, evolutionary most ancient immunocytes, seem to play a special role in communication with enteric neurons. We found that a specialized type of intestinal macrophages is associated with the enteric nervous system. We also observed that GI infection induces new connections between neurons and mucosal immune cells, and these connections fail to develop if macrophages are absent. We hypothesize, that remodeling of the enteric nervous system during infection is a macrophage-driven process, which results in new neuro-immune pathways of conditional ?inflammatory? reflexes. By using intravital imaging and transgenic mouse approach to target functions of intestinal neurons and macrophages, we will explore the biology behind conditional inflammatory reflexes, and examine their role in the recall immune response.